Maximizing the cost-effectiveness of cervical screening in the context of routine HPV vaccination by optimizing screening strategies with respect to vaccine uptake: a modeling analysis

Background Regarding primary and secondary cervical cancer prevention, the World Health Organization proposed the cervical cancer elimination strategy that requires countries to achieve 90% uptake of human papillomavirus (HPV) vaccines and 70% screening uptake. The optimal cervical screening strategy is likely different for unvaccinated and vaccinated cohorts upon national HPV immunization. However, health authorities typically only provide a one-size-fits-all recommendation for the general population. We aimed to evaluate the cost-effectiveness for determining the optimal screening strategies for vaccinated and unvaccinated cohorts. Methods We considered the women population in Hong Kong which has a unique HPV infection and cervical cancer epidemiology compared to other regions in China and Asia. We used mathematical models which comprise a deterministic age-structured compartmental dynamic component and a stochastic individual-based cohort component to evaluate the cost-effectiveness of screening strategies for cervical screening. Following the recommendations in local guidelines in Hong Kong, we considered strategies that involved cytology, HPV testing, or co-testing as primary cervical screening. We also explored the impacts of adopting alternative de-intensified strategies for vaccinated cohorts. The 3-year cytology screening was used as the base comparator while no screening was also considered for vaccinated cohorts. Women’s lifetime life years, quality-adjusted life years, and costs of screening and treatment were estimated from the societal perspective based on the year 2022 and were discounted by 3% annually. Incremental cost-effectiveness ratios (ICERs) were compared to a willingness to pay (WTP) threshold of one gross domestic product per capita (US $47,792). Probabilistic and one-way sensitivity analyses were conducted. Results Among unvaccinated cohorts, the strategy that adds reflex HPV to triage mild cytology abnormality generated more life years saved than cytology-only screening and could be a cost-effective alternative. Among vaccinated cohorts, when vaccine uptake was 85% (based on the uptake in 2022), all guideline-based strategies (including the cytology-only screening) had ICERs above the WTP threshold when compared with no screening if the vaccine-induced protection duration was 20 years or longer. Under the same conditions, HPV testing with genotyping triage had ICERs (compared with no screening) below the WTP threshold if the routine screening interval was lengthened to 10 and 15 years or screening was initiated at ages 30 and 35 years. Conclusions HPV testing is a cost-effective alternative to cytology for vaccinated cohorts, and the associated optimal screening frequency depends on vaccine uptake. Health authorities should optimize screening recommendations by accounting for population vaccine uptake. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-023-02748-3.


Model description
1 Natural history 2 Figure S1 shows the natural history of high-risk HPV (hrHPV) infection and cervical cancer among women in 3 the model. The pathway is the same for each of the hrHPV classes considered in the study, namely HPV-16; 4 HPV-18; HPV-OV ("other vaccine types"), which comprises the other five hrHPVs targeted by the 9vHPV 5 vaccine, namely, 33,45,52,and 58;, which comprises all the non-6 vaccine hrHPVs (i.e., 35,39,51,53,56,59,66,67,68,69,73 and 82). [14] Individuals enter the 7 population without HPV infection at birth and become sexually active as early as age 10. Individuals who are 8 sexually active are susceptible to HPV infection. The force of infection for HPV infection depends on the 9 prevalence of HPV infection in the opposite sex and the formation of sexual partnerships with the opposite sex 10 at different ages and sexual activities, as well as the transmission probability (βh) which is specific to HPV 11 classes. [21,24,25] For women who are infected with HPV, the infection could progress to precancerous states 12 (cervical intraepithelial neoplasia; CIN1, CIN2 and CIN3). The infection may also clear spontaneously in the 13 health states HPV infection, CIN1 and CIN2. We assume that individuals with CIN3 would not recover 14 naturally. Disease progression rates and clearance rates are assumed to depend on HPV type but not age.

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Cervical cancer without symptoms may become symptomatic or progress to more advanced stages of cervical 17 cancer without symptoms. In the absence of screening, cervical cancer is diagnosed only when symptoms 18 develop, in which the patient will be treated accordingly. Women with cervical cancer diagnosed are subjected 19 to the stage-specific probability of cancer-associated death. [26] The progression rates of cervical cancer and 20 cervical cancer-related death rates are assumed to be independent of age, sexual activity level and HPV 21 type. [21] 22 23 The basic compartmental epidemic models based on ordinary differential equations assume that the duration of 24 each compartment is exponentially distributed.
[27] For any given mean duration, the probability that the 25 duration is shorter than the mean is higher in exponential distribution than in more biologically plausible 26 distributions such as Erlang and lognormal distributions. Such a difference would have little effect on disease 27 states milder than CIN3 because their durations are relatively short compared to cervical screening intervals. 28 However, given that the expected duration of CIN3 is much longer (>10 years on average), [28] assuming that 29 the duration of CIN3 is exponentially distributed might artificially lower the effectiveness of cervical screening.

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As such, we assume that the time from CIN3 to asymptomatic cervical cancer is an Erlang-4 distribution.

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We refer to a local study for cervical cancer survival specified by the International Federation of Gynaecologists 35 and Oncologists (FIGO) staging system. [30] The reported 5-year survival rates are 90.9%, 71.0%, 41.7% and 36 7.8% for FIGO stages I, II, III and IV, respectively. Cancer patients who remain alive 5 years after cancer 37 diagnosis are regarded as cancer survivors. [31] In the model, we assume that cancer survivors will not be 38 susceptible to new HPV infection because they may have their uterus and cervix removed with hysterectomy 39 following cancer treatments.

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We assume that transmission probability of HPV infection (βh), HPV regression (τh HPV ) and waning of induced 3 Figure S1. Schematic of the natural history model for high-risk HPV infection and cervical cancer among females.

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Abbreviations: CC1 to CC4, cervical cancer in International Federation of Gynecology and Obstetrics (FIGO) stage I to IV correspondingly; CIN1 to CIN3, cervical 4 intraepithelial neoplasia grade 1 to 3. 5 λh is the force of infection (FOI) for HPV class h. γh X and τh X are the progression and clearance rates for disease state X with HPV class h. wh is the waning rate of natural 6 immunity against HPV class h. The progression of CIN3 to asymptomatic CC1 is assumed to follow an Erlang-4 distribution with mean 1/γh CIN3 , i.e. γh CIN3 = gh CIN3 / 4. An 7 individual may transit to another health state or remain in the same health state. An individual may also experience an age-dependent all-cause mortality rate (m). Colored 8 notations refer to the inferring parameters in model calibration, where λh is affected by the transmission probability (βh). Other notations in black are based on the literature.   (Table S1)    19 20 This balance rule simply states the fact that the number of sexual partnerships that females from stratum (f, a, u) 5 form with males from stratum (m, b, v) is the same as the number of sexual partnerships that males from stratum 6 (m, b, v) form with females from stratum (f, a, u). At any given time t, the degree to which the balance rule is 7 violated could be measured by: To ensure that the balance rule is satisfied at all times, the adjusted contact rates are: 10 11 Following common practice, we choose θ = 0.5 which means that the relevant parameters of females and males 12 are adjusted to the same degree. [34]   13  14  15   , ,  , , , ,  , ,  , ,  ,      types that are targeted by the 9vHPV vaccines, i.e., 33,45,52,and 58. 7 Note. Refer to Table S3 for the definition of the parameters. [19] The guidelines recommend using HPV 34 testing for women aged 30 years or above. Following the guidelines, screening would start at the age of 25 years 35 with cytology as the primary for all screening strategies examined. Under primary HPV test and co-test as 36 primary (i.e., strategies B1-B3 and C1-C3 in Figure S4, respectively), the primary screening would switch to 37 HPV test and co-test at age 30 years, respectively. For co-test strategies, HPV tests would still be performed 38 among women aged 25-29 years as a co-test when they have abnormal cytology. When evaluating the impacts 39 of screening strategies, we assume that alternative strategies will be adopted starting in 2022. For older age 40 cohorts that have already started cervical screening, we assume that they would follow the strategy A1 41 Cytology-only before 2022 and would switch to the alternative strategies afterward.

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For women who would undergo screening in or after the current calendar year, we assume that ( year, we assume that (i) 70% screening uptake among eligible women aged 25-64 years after the 49 commencement of CSP; (ii) among (i), 75% would comply with regular screening, i.e., attending the 3-year 50 screening of cytology-based screening following the initial screening guidelines; and (iii) the rest of (ii) would 51 attend a longer screening interval at 6 years upon receiving consecutive test results. [52,53] For the time before 52 the commencement of CSP, we assume that (i) 40% screening uptake among eligible women aged 25-64 53 years; [52,54,55] (ii) 60% of (i) would comply with a regular screening at 1-, 2-, or 3-year intervals;[52] and 54 (iii) the rest of (ii) will attend the screening at a longer interval of 44 months upon receiving negative test 55 results.
[52] Regarding the relationship between screening preference and individuals' vaccination status, we 56 assume that screening uptake would be the same among vaccinated and unvaccinated individuals.

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Furthermore, currently, the electronic health record systems of immunization and screening in Hong Kong are 59 not linked. [18,56] Joining electronic platforms is voluntary and requires users to initiate registration and 13 consent for sharing corresponding information between the public and private sectors. Alternatively, parents 1 could keep a paper card of immunization for their children. That is, individual-level vaccination characteristics 2 (e.g., age at vaccination and number of doses received) may rely on recall, or the immunization record card if it 3 is still available, when women attend cervical screenings nearly 15-20 years after they were vaccinated in their 4 adolescence. As such, we assume a single screening strategy for both vaccinated and unvaccinated women in the 5 vaccinated cohorts.

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We adopt the findings reported in the meta-analyses for the test performance of cytology and HPV testing (Table   8 S4).[57-61] If screening suggested high-grade lesions, a colposcopic-directed biopsy would be done. Colposcopic 9 directed biopsy is generally considered the reference for diagnosis and therefore we assume that colposcopic 10 directed biopsy to be 100% accurate in the model. We also assume that liquid-based cytology (LBC) instead of 11 conventional cytology would be used, given the advantages that LBC allows the performance of reflex HPV 12 testing and that LBC reduces the rate of unsatisfactory cytology sampling. [19] 13 14 14 Figure S4. Schematic presentation of evaluated cervical screening algorithms that are currently indicated in Hong Kong.
1 2 (a) Primary cytology with a 3-yearly routine screening interval, with two managements for ASCUS cytology test results

(c) Co-test of cytology and HPV test as primary with a 5-yealry routine screening interval, with three managements for normal cytology and HPV test-positive cases
1 T(a, b, c) denotes a triangular distribution that ranges from a to b with mode c.

Cost-effectiveness analysis
To assess the long-term impact of HPV vaccination and cervical screening, we compute the costs and health 1 outcomes associated with cervical cancer over the lifetime of women in each cohort. The age structure and 2 sexual mixing in the stochastic model and the dynamic model are the same. We set the discount rate at 3% 3 annually for both costs and health outcomes and the outcomes were discounted starting from the year 2022. As a 4 sensitivity analysis, we considered annual discount rates at 0% and 6%, and screening participation rates at 50% 5 and 100%. To account for parameter uncertainty, we conduct probabilistic sensitivity analysis (PSA) which 6 includes (i) 100 parameter sets relating to disease epidemiology (e.g., the natural history of HPV transmission, 7 vaccine efficacy and test performance) and (ii) 100 parameter sets on costs and health utilities. A total of 10,000 8 combinations of parameters are sampled using Latin hypercube sampling. We consider the incremental cost-9 effectiveness ratio (ICER), which is defined as the incremental cost divided by the incremental health outcome, 10 when comparing two strategies. That is, ICER= , where Ci and Ei are the mean cost and mean health 11 outcomes of strategy i that are estimated from PSA, respectively. In general, for an increase in health outcomes 12 (i.e., E2 -E1 > 0), strategy 2 is deemed cost-effective if the corresponding ICER is below the willingness to pay 13 (WTP) threshold. When ordering screening strategies, the strategy that has the lowest average cost-effectiveness 14 ratio against the situation of no screening will be ranked first, and then followed by strategies that return the 15 lowest ICERs with the previous non-dominating strategies.
[66] We consider a strategy strongly dominated when 16 it is less effective but more costly than an alternative strategy, and a strategy extendedly (weakly)  9 Table S7 presents the cost-effectiveness of the guidelines-based screening strategies in the scenarios of an 10 annual discount rate at 0% (i.e., undiscounted) and 6%. When the annual discount rate was 0%, the estimated 11 ICERs decreased when compared to the scenario of a 3% annual discount rate in the base case. The estimated 12 ICERs increased when the annual discount rate was 6%.
13 Figure S5 presents the one-way sensitivity analysis for comparing strategy A2 (Cytology + HPV reflex; i.e., 14 using HPV test to triage cytology result of ASCUS) vs A1 (Cytology-only) when LY was the metric for health 15 outcomes. The figure also presents the findings for comparing A1 vs No screening when QALY was the metric 16 for health outcomes.
17 29 Table S11 presents the cost-effectiveness of the guidelines-based screening strategies in the scenarios of an 30 annual discount rate at 0% (i.e., undiscounted) and 6%. When the annual discount rate was 0%, the estimated 31 ICERs decreased when compared to the scenario of a 3% annual discount rate in the base case. Strategy B2 32 (HPV + Genotyping) became cost-effective under the WTP threshold at 1 GDPpc when compared with no 33 screening. The estimated ICERs increased when the annual discount rate was 6%.
34 Figure S6 presents the one-way sensitivity analysis for comparing strategies B2 (HPV + Genotyping) and A1

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(Cytology-only) vs No screening when LY and QALY were the metrics for health outcomes, respectively. 36 Table S12 presents the incremental CEA for the scenario analysis under the assumption that the HPV clearance 37 rate and waning rate of natural immunity in males were 2 times faster than that in females for all HPV classes.

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The findings are based on the PSA with parameter sets that are calibrated to empirical data under this 39 assumption. When the vaccine uptake is 85% and the vaccine provides lifelong protection, the comparative cost-40 effectiveness is comparable to the original setting in which the natural history parameters of HPV infection are 41 assumed the same in both genders. For example, the ICERs of the first non-dominated strategy (compared with 42 no screening) increased by less than 2% when compared to the original setting.  Notes. a Total cost, LY, and QALY, and corresponding differences compared with A1 (cytology-only) are presented per 10,000 individuals. Means and 95% percentile 5 intervals are obtained based on simulation. b ICERs are expressed as the incremental mean cost divided by the incremental mean LY or mean QALY correspondingly, 6 compared with the previous non-dominated strategy. The ICERs of the first non-dominated strategy are compared with no screening. ICERs that are below the WTP 7 threshold at 1 GDPpc (US$47,792) are underlined and highlighted. A strategy is dominated (Dom) if it has higher costs and worse outcomes than an alternative strategy. A 8 strategy is extendedly dominated (ExtDom) if the ICER for the strategy is higher than that of the next more effective, non-dominated alternative strategy. d Assuming that the 9 vaccine uptake was 85% among women via the routine immunization program and that the HPV vaccines provided lifelong protection.

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10 11 12   Notes. a Total cost, LY, and QALY, and corresponding differences compared with A1 (cytology-only) are presented per 10,000 individuals. Means and 95% percentile 3 intervals are obtained based on simulation. b ICERs are expressed as the incremental mean cost divided by the incremental mean LY or mean QALY correspondingly, 4 compared with the previous non-dominated strategy. The ICERs of the first non-dominated strategy are compared with no screening. ICERs that are below the WTP 5 threshold at 1 GDPpc (US$47,792) are underlined and highlighted. A strategy is dominated (Dom) if it has higher costs and worse outcomes than an alternative strategy. A 6 strategy is extendedly dominated (ExtDom) if the ICER for the strategy is higher than that of the next more effective, non-dominated alternative strategy. d Assuming that the 7 vaccine uptake was 85% among women via the routine immunization program and the HPV vaccines provided lifelong protection. 8 9 1 provided lifelong protection, the vaccine uptake was 85%, and the screening uptake was 70%.  Notes. a Total cost, LY, and QALY, and corresponding differences compared with A1 (cytology-only) are presented per 10,000 individuals. Means and 95% percentile 5 intervals are obtained based on simulation. b ICERs are expressed as the incremental mean cost divided by the incremental mean LY or mean QALY correspondingly, 6 compared with the previous non-dominated strategy. The ICERs of the first non-dominated strategy are compared with no screening. ICERs that are below the WTP 7 threshold at 1 GDPpc (US$47,792) are underlined. A strategy is dominated (Dom) if it has higher costs and worse outcomes than an alternative strategy. A strategy is 8 extendedly dominated (ExtDom) if the ICER for the strategy is higher than that of the next more effective, non-dominated alternative strategy. 9 10 11 12 1 Note. a ICERs that are below the WTP threshold at 1 GDPpc (US$47,792) are underlined and highlighted.

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Stopping screening after a predetermined number of lifetime normal screens would be labeled as 'not applicable' (NA). c Total cost, LY, and QALY, and corresponding 4 differences compared with A1 (cytology-only) are presented per 10,000 individuals. Means and 95% percentile intervals are obtained based on simulation. d ICERs are 5 expressed as the incremental mean cost divided by the incremental mean LY or mean QALY correspondingly, compared with the previous non-dominated strategy. The 6 ICERs of the first non-dominated strategy are compared with no screening. ICERs that are below the WTP threshold at 1 GDPpc (US$47,792) are underlined and 7 highlighted. A strategy is dominated (Dom) if it has higher costs and worse outcomes than an alternative strategy. e This indicates the initial guidelines-based strategy B2 8 (HPV + Genotyping) that women start cytology screening at age 25 years, then switch to primary HPV test at 30 years old with a 5-year routine screening interval, and 9 continue to screen under age 65 years upon normal screens.
1 Table S15. Cost-effectiveness of variants of strategy B2 (HPV + Genotyping) for cohorts implemented 2 with the routine vaccination program (vaccinated cohorts) when 9vHPV vaccines provided lifelong 3 protection, the vaccine uptake was 85%, and the screening uptake was 70%.